The major objects of the proposed research are to devise new, improved, practical methods of peptide and phosphate ester bond formation and to develop new amine, hydroxyl, carbosyl, and phosphate protecting groups for use in protein and polynucleotide synthesis. Recent advances include the invention of the vinyloxycarbonyl method of amino and hydroxyl protection and the use of highly activated reagents to convert peptide acids to racemization resistant, stabilized active esters. Application of these methods to both solution and solid phase peptide synthesis is under investigation. The vinyloxycarbonyl method of selective, tertiary amine dealkylation invented in these laboratories is being applied to various problems of pharmaceutical significance. Recent advances include improved syntheses of the important narcotic antagonists, naloxone and EN 1639, and related synthetic analgesics. The use of substituted vinyl chloroformates in both amine protection and amine N-dealkylation is under study. A method for the synthesis of these previously unknown and inaccessible reagents has been developed. Another object is the use of new knowledge on heteroaromatic C-H acidities and the WXYZ scission hypotheses developed in this laboratory: 1) in the facile preparation of a variety of new, potentially useful heterocycles, and 2) in the determination of mechanisms of biological and pharmaceutical activity. A new selective approach to 5- unsubstituted isoxazoles is being developed.